Points to consider for laboratories reporting results from diagnostic genomic sequencing.

Although NGS technologies are well-embedded in the clinical setting for identification of genetic causes of disease, guidelines issued by professional bodies are inconsistent regarding some aspects of reporting results. Most recommendations do not give detailed guidance about whether variants of uncertain significance (VUS) should be reported by laboratory personnel to clinicians, and give conflicting messages regarding whether unsolicited findings (UF) should be reported. There are also differences both in their recommendations regarding whether actively searching for secondary findings (SF) is appropriate, and in the extent to which they address the duty (or lack thereof) to reanalyse variants when new information arises. An interdisciplinary working group considered the current guidelines, their own experiences, and data from a recent qualitative study to develop a set of points to consider for laboratories reporting results from diagnostic NGS. These points to consider fall under six categories: (i) Testing approaches and technologies used, (ii) Approaches for VUS; (iii) Approaches for reporting UF, (iv) Approaches regarding SF; (v) Reanalysis of data & re-contact; and vi) Minors. While it is unclear whether uniformity in reporting across all laboratories is desirable, we hope these points to consider will be useful to diagnostic laboratories as they develop their processes for making decisions about reporting VUS and UF from NGS in the diagnostic context.

Cost effectiveness of newborn screening for cystic fibrosis: a simulation study.

BACKGROUND: Early detection of cystic fibrosis (CF) by newborn screening (NBS) reduces the rate of avoidable complications. NBS protocols vary by jurisdiction and the cost effectiveness of these different protocols is debated. OBJECTIVE: To compare the cost effectiveness of various CF NBS options. METHODS: A Markov model was built to simulate the cost effectiveness of various CF-NBS options for a hypothetical CF-NBS program over a 5-year time horizon assuming its integration into an existing universal NBS program. NBS simulated options were based on a combination of tests between the two commonly used immunoreactive trypsinogen (IRT) cutoffs (96th percentile and 99.5th percentile) as first tier tests, and, as a second tier test, either a second IRT, pancreatic-associated protein (PAP) or CFTR mutation panels. CFTR mutation panels were also considered as an eventual third tier test. Data input parameters used were retrieved from a thorough literature search. Outcomes considered were the direct costs borne by the Quebec public health care system and the number of cases of CF detected through each strategy, including the absence of screening option. RESULTS: IRT-PAP with an IRT cutoff at the 96th percentile is the most favorable option with a ratio of CAD$28,432 per CF case detected. The next most favorable alternative is the IRT1-IRT2 option with an IRT1 cutoff at the 96th percentile. The no-screening option is dominated by all NBS screening protocols considered. Results were robust in sensitivity analyses. CONCLUSION: This study suggests that NBS for cystic fibrosis is a cost-effective strategy compared to the absence of NBS. The IRT-PAP newborn screening algorithm with an IRT cutoff at the 96th percentile is the most cost effective NBS approach for Quebec.

Genetics in health care: an overview of current and emerging models.

BACKGROUND: With advances in genetic and genomic medicine, the optimal integration of genetic services into the health care system remains of major concern in many countries. OBJECTIVES: To review the current organisation of genetic services, mostly in Europe, North America and Australia, explore emerging service delivery models, and probe challenges inherent in the transition process. METHODS: We conducted a literature review of genetics in clinical practice: testing, diagnosis, counselling, and treatment. We examined the basic structures of genetic services, examples of integrated networks, and existing professional resources. We investigated services belonging traditionally in medical genetics as well as those developed for more common diseases. RESULTS: Multidisciplinary specialist clinics and coordinated services appeared to be key to delivering proper care in rare genetic disorders. For oncogenetics, neurogenetics and cardiogenetics, interprofessional collaboration between geneticists and other specialists seemed to be favoured. On the other hand, there was also a tendency toward the integration of genetic services directly into primary care. Among the most pressing challenges was the morphing of paediatric care into adult care. CONCLUSION: The coordination of activities between professionals in first-, second-, and third-line medical care is a primary objective calling for the reconfiguration of professional roles and responsibilities. This entails the forging of new relationships as well as an enhanced sharing of expertise and genetic information, including information regarding services. Barriers to overcome include the redistribution of roles, sharing of data and databases, and the lack of preparedness of non-genetics professionals and of the health care system in general.

Debating clinical utility.

The clinical utility of genetic tests is determined by the outcomes following test use. Like other measures of value, it is often contested. Stakeholders may have different views about benefits and risks and about the importance of social versus health outcomes. They also commonly disagree about the evidence needed to determine whether a test is effective in achieving a specific outcome. Questions may be presented as factual disagreements, when they are actually debates about what information matters or how facts should be interpreted and used in clinical decision-making. Defining the different issues at stake is therefore an important element of policy-making. Key issues include evidence standards for test use, and in particular, the circumstances under which prospective controlled data should be required, as well as evidence on feasibility, cost and equitable delivery of testing; the goals of population-based screening programs, and in particular, the role of social outcomes in evaluating test value; and the appropriate uses and funding of tests that inform non-medical actions. Addressing each of these issues requires attention to stakeholder values and methods for effective deliberation that incorporate consumer as well as health professional perspectives.

Assessing the potential success of cystic fibrosis carrier screening: lessons learned from Tay-Sachs disease and beta-thalassemia.

OBJECTIVE: The objective of this study was to identify factors involved in the success of 2 well-established population-based carrier screening programs - Tay-Sachs disease (TSD) in Ashkenazi Jews and beta-thalassemia in Sardinia and Cyprus - and to assess the potential for success of a population-based cystic fibrosis (CF) carrier screening strategy using these factors. METHODS: We performed a literature review and key informant interviews. RESULTS: Factors involved in the success of TSD and beta-thalassemia carrier screening programs include disease characteristics (well-defined population at risk, severe disease with predictable course, availability of effective treatment), test characteristics (high sensitivity, straightforward interpretation of results), and community characteristics (involvement of community, support of families and advocacy groups, consensus in favor of avoiding affected births). Current CF screening strategies include few of the factors listed above. Unlike TSD and beta-thalassemia, the purpose of current CF carrier screening strategies is informed reproductive decision-making, without an explicit goal of reducing disease incidence. CONCLUSION: When compared to TSD and beta-thalassemia, CF is a less favorable candidate for population-based carrier screening. Because of its different purpose, CF carrier screening will require different measures of success than those used for TSD and beta-thalassemia carrier screening, and a consensus on the value or success of CF carrier screening may be difficult to achieve.

Population history and its impact on medical genetics in Quebec.

Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French-Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle-France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix-Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French-Canadian-type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).

[Collaboration between family physicians and home care professionals. Is it possible?]. / Collaborations entre les médecins de famille et les équipes de maintien à domicile. Est-ce possible?

OBJECTIVE: To describe perceptions of physicians and home care professionals working in local community service centres (CLSCs) with respect to collaboration on home care follow up, and to identify conditions likely to help or hinder cooperation. DESIGN: Descriptive study using individual and group interviews. SETTING: Areas served by three CLSCs in the Quebec city region. PARTICIPANTS: Forty-five general practitioners with large home care practices and coordinators and representatives of CLSC home care teams. MAIN OUTCOME MEASURES: Perceptions of physicians and home care professionals with respect to interprofessional cooperation on and barriers to home care follow up. RESULTS: Most participants thought that cooperation would be beneficial to complex case management and continuity of follow-up care. In practice, however, cooperation is hindered by differences in medical practice and home care team service delivery and in methods of remuneration, and lack of knowledge of the other field of practice. CONCLUSION: All participants recognized the importance of cooperation. This study did not reveal any real integration of medical and CLSC home care services. Efforts must be made to identify the strategies most conducive to improving interprofessional cooperation.

[Delivery of home health care. Survey of the Quebec region]. / La prestation de soins médicaux à domicile. Sondage dans la région du Québec.

OBJECTIVE: To describe the characteristics of home health care delivered by general practitioners and to identify the conditions that facilitate or hinder development of this practice. DESIGN: Mailed survey. SETTING: Quebec city region. PARTICIPANTS: General practitioners in private practice, family practice units, community health centres, or hospitals. MAIN OUTCOME MEASURES: A self-administered questionnaire was used to gather information on volume of home care provided, characteristics of clients and visits, methods of follow up, and factors that promoted or hindered home care. RESULTS: Of the 487 physicians surveyed, 58.1% (283) made housecalls to a clientele consisting mainly of elderly patients (87.6%): 42% saw fewer than five patients per week, and 31% spent 2 hours or less per week on housecalls. Close to two thirds (64%) devoted 15 to 30 minutes to these visits, and 90.2% said they used community health centres for assessment or home follow up of their patients. Difficulties with scheduling and methods of remuneration reportedly hampered development of this practice. CONCLUSION: Home care practice is widespread around Quebec city, but represents only a small portion of the clinical work of many GPs.

Which physicians make home visits and why? A survey.

BACKGROUND: Recent changes in the North American health care system and certain demographic factors have led to increases in home care services. Little information is available to identify the strategies that could facilitate this transformation in medical practice and ensure that such changes respond adequately to patients' needs. As a first step, the authors attempted to identify the major factors influencing physicians' home care practices in the Quebec City area. METHODS: A self-administered questionnaire was sent by mail to all 696 general practitioners working in the Quebec City area. The questionnaire was intended to gather information on physicians' personal and professional characteristics, as well as their home care practice (practice volume, characteristics of both clients and home visits, and methods of patient assessment and follow-up). RESULTS: A total of 487 physicians (70.0%) responded to the questionnaire, 283 (58.1%) of whom reported making home visits. Of these, 119 (42.0%) made fewer than 5 home visits per week, and 88 (31.1%) dedicated 3 hours or less each week to this activity. Physicians in private practice made more home visits than their counterparts in family medicine units and CLSCs (centres locaux des services communautaires [community centres for social and health services]) (mean 11.5 v. 5.8 visits per week), although the 2 groups reported spending about the same amount of time on this type of work (mean 5.6 v. 5.0 hours per week). The proportion of visits to patients in residential facilities or other private residences was greater for private practitioners than for physicians from family medicine units and CLSCs (29.7% v. 18.9% of visits), as were the proportions of visits made at the patient's request (28.0% v. 14.2% of visits) and resulting from an acute condition (21.4% v. 16.0% of visits). The proportion of physicians making home visits at the request of a CLSC was greater for those in family medicine units and CLSCs than for those in private practice (44.0% v. 11.3% of physicians), as was the proportion of physicians making home visits at the request of a colleague (18.0% v. 4.5%) or at the request of hospitals (30.0% v. 6.8%). Physicians in family medicine units and CLSCs did more follow-ups at a frequency of less than once per month than private practitioners (50.9% v. 37.1% of patients), and they treated a greater proportion of patients with cognitive disorders (17.2% v. 12.6% of patients) and palliative care needs (13.7% v. 8.6% of patients). Private practitioners made less use of CLSC resources to assess home patients or follow them. Male private practitioners made more home visits than their female counterparts (mean 12.8 v. 8.3 per week), although they spent an almost equal amount of time on this activity (mean 5.7 v. 5.2 hours per week). INTERPRETATION: These results suggest that practice patterns for home care vary according to the physician's practice setting and sex. Because of foreseeable increases in the numbers of patients needing home care, further research is required to evaluate how physicians' practices can be adapted to patients' needs in this area.

[Relationship between preoperative delay in hip fractures, postoperative complications and risk of death]. / Relation entre le délai pré-opératoire pour une fracture de hanche, les complications post-opératoires et le risque de décès.

The objective was to describe the relationship between preoperative delay, postoperative complications, and risk of death at 6 months. The population is constituted of 200 subjects aged 65 years or older who were living at home and treated for a hip fracture in any of three of Québec's hospitals between April, 1st, 1987 and March, 31, 1989. Chi-square or F-test, and linear and logistic regression were used to test the relationship between the variables. Preoperative delays varied from 2 to 403 h (median, 45 h). Variations between hospitals were particularly important; median delay at hospital 1 was 109 h, at hospital 2, 36 h, at hospital 3, 30.5 h. Only 5% of the variance of the delay was explained by the subjects' characteristics before the fracture. The relationships between delay and postoperative complications are not significant. However, the risk of death at 6 months increased with the length of operative delay; the observed increase tends to be linear (p = 0.03). These results suggest first, that surgery for hip fracture had to be consider as an urgency, second, that it could be done 36 hours or less after the arrival at hospital.

Structural characterizations of neuropeptide tyrosine (NPY) and its agonist analog [Ahx5-17]NPY by NMR and molecular modeling.

The structures of human NPY and of its centrally truncated agonist analog [Ahx5-17]NPY have been investigated in DMSO-d6 by two-dimensional NMR and by molecular modeling. For both peptides, a complete resonance assignment was achieved and a large number (more than 200) of inter-residue NOE connectivities were observed, including long-range connectivities between the N- and C-terminal ends of the chain. Molecular models were calculated using NOE constraints by distance geometry, simulated annealing and conjugate gradient energy minimization. The results indicate that both peptides are folded in the center of their chain, NPY adopting the hairpin shape, whereas the central portion of [Ahx5-17]NPY is characterized by relatively large loops. In contrast to previous models, practically no alpha-helical structure exists for these peptides under our conditions, but two beta-turns are found in NPY and one in [Ahx5-17]NPY. The proximity of the terminal ends could be the determinant factor for their activity.

[Variations in the incidence of fractures of the upper part of the femur in aged persons in the Quebec region]. / Variations de l'incidence des fractures de l'extrémité supérieure du fémur chez les personnes âgées de la région de Québec.

To estimate the incidence of fracture of the proximal end of the femur in people aged 50 years or older living in the Quebec area in 1971, 1976 and 1981 we determined the number of admissions for such fractures to the 15 acute care hospitals in the region. From 1971 to 1981 the number of fractures increased by 71%; the increases for those aged 75 to 84 years and 85 years or over were 98% and 118% respectively. The variation is only partly explained by changes in sex and age distribution of the population; the incidence rates also increased. Among men aged 75 to 84 years the incidence rate per 1000 person-years rose from 2.63 in 1971 to 5.22 in 1981, an increase of 98%; the corresponding figures for men aged 85 years or more were 9.76 and 16.91, an increase of 73%. Among women aged 75 to 84 years the rate rose from 7.28 to 8.81, an increase of 21%; the corresponding figures for women aged 85 years or more were 20.40 and 24.27, an increase of 21% and 19% respectively.

Preparation of leukocyte-poor blood: a comparison of IBM 2991 washing and Huggins freeze-thawing.

Frequently, forzen blood is requested in order to provide a leukocyte-poor red cell transfusion and a reduced level of exposure to hepatitis virus rather than in an effort to find serological compatible red blood cells. However, this usage of frozen blood is expensive and, as recently reported, does not eliminate the risk of transmission of hepatitis. To assess the feasibility of substituting washed cell preparations, we have compared the Huggins frozen blood process with the IBM 2991 cell washing technique and have evaluated the efficiency of leukocyte removal and red cell recovery from homologous pools of fresh blood. The results of these experiments combined with the greatly decreased cost (approximately 1/3) and time required (approximately 1/6) indicate that many of the requests which blood banks receive for frozen blood could, in fact, be better met by using cells which have been washed in the IBM 2991.